1. HIV and Malaria Dr Jane Achan Dept of Pediatrics, Makerere University College of Health Sciences Prof. Moses Kamya Makerere University College of Health Sciences 6 th IAS CONFERENCE, 18 th July 2011

2. Burden of malaria Over 300 million clinical cases and 1 million deaths annually Accounts for 25-40% of outpatient visits and 20-50% of hospital admissions

3. HIV and Malaria in Sub-Saharan Africa HIV distributionMalaria distribution

4. Epidemiological overlap: Why does this matter? Any interaction could be of great pubic health importance: – Malaria could accelerate HIV disease progression and facilitate HIV transmission – HIV infection could disrupt immune responses to malaria and may increase incidence and severity of malaria – Routine interventions for HIV may impact upon the incidence of malaria – Therapies for each infection may impact upon the other, leading to unanticipated effects on drug efficacy or toxicity

5. Plausibility of interaction: Malaria affecting HIV Antigen stimulationImmune activation Faster disease progression Increased viral replication

6. HIV Viral load changes during malaria. Hoffman et al, AIDS. 13(4):487-494, March 11, 1999.

7. Influence of malaria on HIV disease Increased viral load during malaria might be sustained for long enough to increase risk of HIV transmission and accelerated disease progression. Parasitemia and clinical malaria are associated with 0.25-0.89 log increase in viral load for about 9 weeks Treatment of malaria in HIV-infected adults is associated with decreased viral load (190000 to 120000 copies/ml) Kublin, et al, Lancet 2005;365:233-239; ter Kuile, et al, Am J Trop Med Hyg 2004;71:41-54; Van Geertruyden, et al, JAIDS 2006;43:363-7; Hoffman, et al,AIDS 1999;13:487-495; Mermin, et al, JAIDS 2006;41:129-130, Brahmbhatt, et al, AIDS 2003; 17: 2539-41; Ayisi, et al, AIDS 2003; 17: 585-94; Ned, et al, Trends Parisitol 2005;24: 285-91., tatfeng et at, J Vector Borne Dis 44, June 2007

8. Influence of malaria on HIV disease Malaria associated with more rapid decline in CD4 cell count – Mean difference in CD4 cell decline per additional episode of malaria was 40 cells/µL/year (Mermin et al, JAIDS 2006;41:129-130) However evidence that malaria has an impact on HIV disease progression is limited Transient and repeated increases in HIV viral load from recurrent co-infection with malaria may contribute to promoting the spread of HIV in sub-Saharan Africa. – Modelling in Kisumu, Kenya indicated a 2.1% increase in HIV prevalence since 1980. Abu-Raddad, et al, Science 2006;314:1603-1606;

9. HIV and malaria in pregnancy Pregnant women are at increased risk for malaria, especially in their first 2 pregnancies. Estimated that the HIV epidemic results in an additional 500,000 to 1 million women per year who have malaria during pregnancy ●HIV infected pregnant women are at increased risk of: –Symptomatic malaria and placental malaria –Severe malaria –Maternal anemia and adverse birth outcomes Malaria infection placental malaria low birth weight infant mortality maternal anemia

10. Total n = 414: Kisumu, Kenya, 1994-1996 (CDC Studies) Gravidity-related pattern of Malaria in pregnancy is altered by HIV

11. Gravidity-related pattern of Malaria in pregnancy ●The gravidity-related pattern of Malaria in pregnancy is altered by HIV so that the burden is shifted from primigravidae to all pregnant women ●Possible mechanism: HIV may affect memory immune mechanism in pregnant women → parity dependent acquisition of anti-malarial immunity

12. MTCT and Infant outcomes Infant Mortality Rate (IMR) increases in HIV+ pregnant women with malaria Mother to child transmission (MTCT) of HIV increased when women had placental Malaria Brahmbhatt, et al, AIDS 2003; 17: 2539-41; Ayisi, et al, AIDS 2003; 17: : 585-94 Postnatal death in infants is higher amongst HIV positive women with placental malaria compared to HIV positive women (Odds Ratio: 3 – 7.7; Bloland, Malawi.95)

13. SP- IPT versus CTX for prevention of malaria in pregnancy

14. “Combination prevention” for malaria in HIV infected populations. ● Cotrimoxazole prophylaxis (CTX) ● Insecticide treated bed nets (ITNs) ● ART

15. Malaria incidence among HIV-infected adults ●95% reduction in malaria with all 3 interventions Malaria per 100 person- years

16. Effect of CTX and ITN use on malaria incidence (Kamya et al. AIDS 2007) Exposure GroupIRR (95% CI)P-value No CTX, No ITNReference group CTX prophylaxis alone0.65 (0.27-1.57)0.34 ITN alone0.56 (0.45-0.70)<0.001 Both CTX and ITN0.03 (0.01-0.11)<0.001

17. Protective efficacy of CTX in Kampala over time Time periodMalaria incidence (PPY)Protective efficacy IRR (95% CI)* No TS TS Aug 06-Jan 070.110.710.16 (0.09-0.27) Feb 07-Jul 070.140.510.28 (0.16-0.46) Aug 07 – Jan 08 0.090.380.24 (0.13-0.46) * Test for trend: p-value = 0.35

18. Prophylactic effect of CTX against malaria in contrasting transmission settings Site CTX use Episodes of malaria Person time Incidence of malaria (PPY) IRR (95% CI) Kampala * No CTX 3897270.54 0.20 (0.13-0.30) CTX494230.12 Tororo ‡ No CTX 12144.12.74 0.27 (0.19 -0.40) CTX4566.30.68 * low-medium transmission site; ‡ very high transmission site

19. Clinical implications ●Malaria is rarely the cause of fever in individuals receiving CTX ●Malaria accounted for only 4% of febrile episodes in an HIV- infected cohort compared to 33% in the HIV- uninfected cohort (p < 0.0001). Kamya et al, AIDS, 2007 ●Presumptive therapy for malaria in these groups should be avoided and careful evaluation for other causes of fever should be done

20. Are we creating resistance?

21. HIV and Malaria Interactions DON’T FORGET THE DRUGS!

22. AQ/AS AL AQ Exposure ¹ Liver Function Tests ¹ Moderate to severe neutopenia ² HIV Infected Children Antiretrovirals (nucleoside analogues) On going study Healthy Volunteers Efavirenz Healthy Volunteers Lopinavir / ritonavir Healthy Volunteers Lumefantrine ³ Exposure (200%) ¹ German, etal CID, 2007 ² Gasasira, etal CID, 2008 ³ German, etal 15 th Croi, 2008

23. Conclusions ●Significance of the impact of malaria on HIV disease progression remains to be determined especially in this era of malaria preventive strategies. ●Malaria prevention in pregnancy is critical to minimize adverse pregnancy outcomes. ●There is strong evidence for the impact of combination prevention against malaria in HIV infected populations ●Attention to drug-drug interactions is critical as new antimalarial and antiretroviral drugs are rolled out.

24. Acknowledgements ●Makerere University-University of California San Francisco (MU-UCSF) Research Collaboration: –Diane Havlir –Edwin Charlebois –Grant Dorsey –Philip J Rosenthal ●Sponsors: NIH, NICHD, CFAR ●Staff, Patients and caretakers that contribute to these studies

25. Thank You